Suhonen P, Järvinen T, Lehmussaari K, Reunamäki T, Urtti A
Department of Pharmaceutical Technology, University of Kuopio, Finland.
Pharm Res. 1995 Apr;12(4):529-33. doi: 10.1023/a:1016297728396.
The influence of buffer, viscosity and cyclodextrin on the ocular absorption and irritation of a pilocarpine prodrug, O,O'-dipropionyl-(1,4-xylylene) bispilocarpic acid diester, was studied in albino rabbits. The prodrug solutions, equivalent to 0.5% pilocarpine, were prepared in 0, 10, 20, 50, or 75 mM citrate buffer at pH 5.0. Viscosity of the solutions (20, 50 or 115 cP) was modified with hydroxypropyl methylcellulose. 2-hydroxypropyl-beta-cyclodextrin (HPCD) was included at concentrations 5, 10 and 15% (w/v). The formulations were compared to a commercial pilocarpine eyedrop (1.7%). Ocular irritation was graded in a double-masked experiment and miosis was used as a bioassay for pilocarpine delivery to the iris. The prodrug showed decreased peak and prolonged duration of miosis compared to pilocarpine, but it caused ocular irritation. Increasing buffer strength decreased and elevated viscosity intensified the miotic response and irritation by the pilocarpine prodrug. HPCD decreased both the ocular delivery of pilocarpine and the irritation by the prodrug, but the net effect was positive. Thus, administering 1.0% of pilocarpine as a prodrug with 15% (w/v) HPCD, the irritation was at the same level with the commercial pilocarpine eyedrop, but the ocular delivery was substantially improved. In conclusion, the ocular delivery of the pilocarpine prodrug may be enhanced in relation to its local irritation by properly combining buffer, viscosity and HPCD.
在白化兔中研究了缓冲液、粘度和环糊精对毛果芸香碱前药O,O'-二丙酰基-(1,4-亚二甲苯基)双毛果芸香酸二酯眼部吸收和刺激的影响。制备了相当于0.5%毛果芸香碱的前药溶液，分别置于pH 5.0的0、10、20、50或75 mM柠檬酸盐缓冲液中。用羟丙基甲基纤维素调节溶液的粘度（20、50或115 cP）。2-羟丙基-β-环糊精（HPCD）的浓度分别为5%、10%和15%（w/v）。将这些制剂与市售毛果芸香碱滴眼液（1.7%）进行比较。在双盲实验中对眼部刺激进行分级，并将瞳孔缩小用作毛果芸香碱递送至虹膜的生物测定。与毛果芸香碱相比，前药的瞳孔缩小峰值降低且持续时间延长，但会引起眼部刺激。增加缓冲强度会降低，而提高粘度会增强毛果芸香碱前药的缩瞳反应和刺激。HPCD降低了毛果芸香碱的眼部递送以及前药引起的刺激，但总体效果是积极的。因此，将1.0%的毛果芸香碱作为前药与15%（w/v）的HPCD一起给药时，刺激程度与市售毛果芸香碱滴眼液相同，但眼部递送有显著改善。总之，通过适当组合缓冲液、粘度和HPCD，毛果芸香碱前药的眼部递送相对于其局部刺激可能会得到增强。
